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Biomedical subjects

R A Knight

Publications and source records attributed to R A Knight.

At least 73 records · Page 4Linked to original sources
PubMed1997

Retinoids and the control of growth/death decisions in human neuroblastoma cell lines.

Cell proliferation, the balance between mitosis and apoptosis is the result of the continuous integration of a number of different signal transduction pathways stimulated in a cell at any given point in its life. Neuroblastoma cells regulate the switch between mitosis and death, according both to intrinsic factors and extrinsic factors, such as growth factor withdrawal and action of the vitamin A derivative, retinoic acid. In this review, we describe the balance of some factors regulating growth and death of human neuroblastoma cells in vitro. These dynamic studies are necessarily-performed on cell lines, which offer controlled conditions enabling the disection of the complex stimuli mediating survival and growth (IGF, trk, BDNF) and death (transglutaminase, free radicals, Bcl-2). Although the conclusions drawn may therefore not be directly applicable to tumour cells in vivo, the results herein discussed are of sufficient significance to warrant in vivo relevance.

Cell Death↗
PubMed1997

Recidivism rates among child molesters and rapists: a methodological analysis.

We address the high variability in sex offender recidivism rates by examining several of the critical methodological differences that underlie this variability. We used a dataset on 251 sex offenders (136 rapists and 115 child molesters) who were discharged over a 25-year period to examine changes in recidivism as a function of changes in dispositional definition of reoffense (e.g., arrest or conviction), changes in the domain of criminal offenses that are considered, and changes in the length of exposure time. The data indicate that: (a) both rapists and child molesters remain at risk to reoffend long after their discharge, in some cases 15-20 years after discharge; (b) there was a marked underestimation of recidivism when calculating a simple proportion (%) consisting of those who were known to have reoffended during the follow-up period, and (c) there was a marked underestimation of recidivism when the criterion was based on conviction or imprisonment. Forensic, clinical and policy implications of this high variability are discussed.

Adolescent↗
PubMed1997

Risk factors associated with recidivism among extrafamilial child molesters.

This study examined the predictive efficacy of 10 rationally derived, archivally coded variables for assessing reoffense risk among extrafamilial child molesters. Follow-up data on 111 child molesters who were discharged from the Massachusetts Treatment Center between 1960 and 1984 were used. Degree of sexual preoccupation with children, paraphilias, and number of prior sexual offenses predicted sexual recidivism. Juvenile and adult antisocial behavior, paraphilias, and low amount of contact with children predicted nonsexual victim-involved and violent recidivism. Area under the receiver-operating characteristic curves in all three analyses indicated discrimination that was substantially better than chance, ranging from .73 to .79.

Adult↗
PubMed1997

Interferon-gamma (IFN-gamma) down-regulates the rhinovirus-induced expression of intercellular adhesion molecule-1 (ICAM-1) on human airway epithelial cells.

Human rhinoviruses (HRV) are a major cause of upper respiratory tract infections in man, and can exacerbate existing pulmonary disease. The major group of HRV attach to ICAM-1, which is expressed on nasal and bronchial epithelial cells. To study the influence of biological mediators on ICAM-1 expression, and consequently HRV attachment and infection, we compared the effects of various cytokines, alone and in combination, on ICAM-1 expression by an uninfected and HRV-infected bronchial epithelial cell line H292. Cytokines known to be released soon after viral infection, such as tumour necrosis factor-alpha (TNF-alpha), IL-1beta and the chemokine IL-8 increase ICAM-1 expression on uninfected cells. Epithelial cells infected with live HRV-14 displayed marked up-regulation of ICAM-1 compared with baseline. TNF-alpha further enhanced the HRV-induced increase in ICAM-1 expression on epithelial cells, peaking at day 4 after infection, whilst IL-8 exhibited a steady increase in ICAM-1 expression over 14 days. In contrast, IFN-gamma, a known Th1 antiviral lymphokine, whilst increasing the level of ICAM-1 on uninfected cells, induced a significant persistent down-regulation of ICAM-1 expression on HRV-infected epithelial cells. With combinations of TNF-alpha and IFN-gamma, ICAM-1 expression on HRV-infected cells was reduced to basal levels. The effects of IFN-gamma were paralleled by a reduction in viral titres. Our in vitro model has provided useful insights into the early pathogenic events of HRV infection at the level of the host cell-virus interaction. Our data confirm that biological mediators play a crucial role in the pathogenesis as well as the course of HRV infection which is modulated by the types, and time kinetics of inflammatory cytokines in the immediate microenvironment.

Bronchi↗
PubMed1997

Defective antigen presentation by lavage cells from terminal patients with cystic fibrosis.

Macrophages separated from lavage samples obtained from lungs removed at transplantation from patients with cystic fibrosis (CF) and other lung diseases, have been compared with circulating monocytes from the same patients for their ability to stimulate allogeneic normal circulating lymphocytes and to present antigen to autologous hilar lymph node cells. In general, macrophages separated from lavage samples from CF patients were unable to stimulate allogeneic lymphocytes and to present antigen, although monocytes from the same patients were functional in both assays. In contrast, lavage cells from non-CF patients were generally effective in both allogeneic stimulation and antigen presentation. These data suggest that immune cells within the lungs of CF patients are functionally compromised, a deficiency which may contribute to the recurrent infections characteristic of the disease.

Antigen Presentation↗
PubMed1997

Mitogenic response and steroid sensitivity in MS lymphocytes.

OBJECTIVES: We investigated mitogenic response and steroid sensitivity in multiple sclerosis (MS) lymphocytes to establish if MS lymphocytes were less steroid responsive. MATERIAL AND METHODS: We compared mitogenic response to phytohaemagglutinin (PHA) and inhibition by dexamethasone (DEX) in circulating lymphocytes from both MS patients and healthy subjects. RESULTS: We found a range of responses in each group but no significant differences between the two groups, nor in patients with and without enhancement on magnetic resonance imaging. The mid-inhibitory concentration of DEX in response to 1 microg/ml PHA was significantly lower than that for 2.5 microg/ml PHA in the patients. The mid-inhibitory concentrations of DEX in response to 2.5 microg/ml PHA negatively correlated with endogenous serum cortisol concentrations. CONCLUSION: These data imply a spectrum of glucocorticoid response that is similar in normal and MS lymphocytes and can partly explain why response to steroid therapy is variable.

Adult↗
PubMed1996

Dot Enumeration Perceptual Organization Task (DEPOT): evidence for a short-term visual memory deficit in schizophrenia.

The Dot Enumeration Perceptual Organization Task (DEPOT) evaluates the validity of 2 specific competing cognitive models of early input dysfunction in schizophrenic individuals: a primary Stage 1, sensory store, perceptual organization deficit vs. a Stage 2, short-term visual memory (STVM) deficit. DEPOT was also designed to assess the hypothesis that schizophrenic individuals tend to perform poorly on all cognitive tasks. In DEPOT both number and form judgments are made about the same dot patterns. A response delay manipulation assesses the persistence and operation of STVM. The study included 41 psychotic inpatients (8 with acute and 16 with chronic schizophrenia and 7 with bipolar and 10 with nonbipolar affective disorder) and 38 controls (22 college students and 16 hospital personnel). Although the pattern of results was consistent with neither the Stage 1 deficit nor the general deficit hypotheses, a Stage 2, STVM deficit hypothesis could account parsimoniously for the data.

Adult↗
PubMed1996

Stimulus configuration and context effects in perceptual organization in schizophrenia.

Two studies assessed perceptual organization in schizophrenia to determine (a) whether inpatient and outpatient groups with poor premorbid schizophrenia have comparable levels of perceptual organization deficit; and (b) whether the deficit could be eliminated by task manipulations. In Study 1, inpatients demonstrated clear evidence of a perceptual organization deficit, whereas outpatients performed similarly to the control groups. In Study 2, a performance pattern that operationally defined a perceptual organization deficit was eliminated by a task manipulation thought to aid in context processing. The perceptual organization deficit is most pronounced in actively symptomatic patients with poor premorbid schizophrenia, and the deficit reflects, in part, deficient top-down influences to basic perceptual processes.

Adult↗
PubMed1996

Reduced top-down influence in auditory perceptual organization in schizophrenia.

Perceptual organization of auditory information is influenced by both the physical characteristics and the categorization of irrelevant information. This study sought to determine the degree to which schizophrenia patients could utilize acoustic properties and contextual cues (top-down factors) to segregate relevant from irrelevant material in an auditory stream. On a modification of I. Neath, A. M. Surprenant, and R. G. Crowder's (1993) auditory suffix task, both schizophrenia and control participants demonstrated better recall of relevant information when irrelevant information had different physical characteristics, compared with when both arose from the same source. In contrast, schizophrenia patients were unaffected by a contextual manipulation that allowed controls to reduce the interfering effect of an irrelevant stimulus. These data suggest that a reduced ability to utilize contextual information plays a role in the perceptual organization dysfunction in schizophrenia.

Adult↗
PubMed1996

In vivo effects of recombinant human DNase I on sputum in patients with cystic fibrosis.

BACKGROUND: Viscoelastic secretions in cystic fibrosis cause impaired mucus clearance and persistence of bacteria within the lung. The abnormal rheology is partly due to the presence of high molecular weight deoxyribonucleic acid (DNA). Recombinant human DNase I (rhDNase) has been shown to depolymerise DNA and thereby reduce the in vitro viscoelasticity of sputum in patients with cystic fibrosis. A phase II double blind placebo controlled study showed that rhDNase improved pulmonary function in patients with cystic fibrosis. The object of the present study was to evaluate the in vivo effects of rhDNase on sputum rheology and to determine whether these were correlated with changes in pulmonary function. METHODS: Patients were randomised to receive either placebo or rhDNase 2.5 mg twice daily for 10 days. Sputum samples were collected in sterile containers during screening and during treatment with the study drug. Pulmonary function and rheological analysis were the primary outcomes evaluated. Other parameters assessed were quantitative sputum bacteriology, sputum DNA concentration, and change in molecular mass of DNA polymers. RESULTS: The viscoelasticity of the sputum in untreated patients with cystic fibrosis was high and treatment with rhDNase reduced all the rheological parameters measured: dynamic storage modulus (a measure of elasticity), dynamic loss modulus (a measure of viscosity), and log complex modulus (a measure of mucus rigidity). The calculated cough clearance index was also improved following treatment with rhDNase. These rheological parameters showed a correlation with forced expiratory volume in one second (FEV1) which was improved by a mean (SE) of 13.3 (5.6)% on day 10 of treatment with rhDNase compared with a change of 0.2 (3.1)% in the placebo group. There was no change in bacterial colony counts or sputum DNA concentrations following treatment with rhDNase, but a small decrease in high molecular weight DNA was observed. CONCLUSIONS: Patients with cystic fibrosis treated with rhDNase show an improvement in rheological properties and pulmonary function, one of the mechanisms being a reduction in the proportion of high molecular weight DNA.

Adolescent↗
PubMed1996

Pulmonary sarcoidosis: patterns of cytokine release in vitro.

This study was designed to investigate the ability of bronchoalveolar and blood mononuclear cells to produce inflammatory mediators in vitro in pulmonary sarcoidosis. Seventeen patients with pulmonary sarcoidosis (stage I n = 8; stage II/III n = 9) and 10 normal controls were investigated. Bronchoalveolar and peripheral blood mononuclear cells were cultured in serum-free medium, without stimulant, for 24 h, and the supernatants analysed for concentrations of interleukin (IL)-1 beta (IL-1 beta), IL-2, IL-6, tumour necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma) and neopterin. Bronchoalveolar lavage cells (BALC) of sarcoid patients released significantly higher amounts of TNF-alpha, IL-6, IFN-gamma and neopterin in comparison to normal controls. When smokers were excluded, there was also an increased release of IL-1 beta and GM-CSF. In the sarcoid group, the levels of IL-1 beta, IL-6, TNF-alpha and GM-CSF showed highly significant correlations between each other, but not with IL-2, IFN-gamma or neopterin. Sarcoid patients whose BALC released more TNF-alpha or GM-CSF had higher percentage counts of alveolar macrophages but fewer lavage lymphocytes. In sarcoid patients, peripheral blood mononuclear cells (PBMNC) also released higher amounts of IL-1 beta, TNF-alpha, IL-6 and GM-CSF but less neopterin than normal controls. Patients whose PBMNC produced more IL-1 beta, IL-6 and GM-CSF had higher absolute and relative lavage neutrophil counts. No relationships were observed between cytokine release and radiographic or physiological markers of disease severity. We conclude from this study that sarcoid inflammation is associated with an increased and concerted release of monocyte/macrophage-derived cytokines not only in the lung but also in the peripheral blood. We speculate that the lymphokines, IFN-gamma and IL-2, are not the primary triggers.

Adult↗
PubMed1996

The effects of recombinant human DNase on neutrophil elastase activity and interleukin-8 levels in the sputum of patients with cystic fibrosis.

In cystic fibrosis (CF), neutrophil-dominated airway inflammation results in high levels of neutrophil elastase (NE). Some of these proteases are sequestered by the large amounts of deoxyribonucleic acid (DNA) present in purulent sputum. Recombinant human deoxyribonuclease (rhDNase), a new treatment in CF, depolymerizes DNA. Our concerns were that this might release proteases bound to DNA, which could be potentially harmful. The in vitro and in vivo effects of rhDNase on NE and interleukin-8 (IL-8) were evaluated. The acute effects of rhDNase were evaluated in CF patients during the first 6 days of treatment. Medium-term effects were evaluated in stable CF patients observed in rhDNase over 6 months. Sputum samples were collected at regular intervals and NE activity was measured by a fluorimetric assay and IL-8 with a radioimmunoassay. In vitro addition of rhDNase resulted in a twofold increase in protease activity and this was reflected in an acute transient rise on initiation of treatment with rhDNase. Medium-term treatment was associated with a decline in NE activity and IL-8. These in vivo results are encouraging, since the increase in protease activity was transient and the trend over 6 months was a reduction in both inflammatory markers.

Cystic Fibrosis↗
PubMed1995

Tamoxifen and somatostatin affect tumours by inducing apoptosis.

Tamoxifen is a commonly used chemotherapeutic agent in human breast cancer, although some tumours develop resistance. Somatostatin is also being introduced as an anti-tumour agent. Here we show that the action of these drugs is, at least partly, due to their induction of apoptosis. Both 50 nM somatostatin, and 60 nM tamoxifen significantly enhanced the percentage of cells undergoing apoptosis, when compared to untreated or oestrogen treated control cells. This effect was observed in SK-N-BE(2) human neuroblastoma cells and in MCF-7G human breast cancer cells but not in their drug-resistant counterpart MCF-7A which showed a very low rate of spontaneous programmed cell death. Finally, we propose a simple test of the sensitivity and resistance of individual tumours to these agents by assessing their ability to induce apoptosis in vitro as measured by flow cytometry.

Antineoplastic Agents↗
PubMed1995

A model to predict the histopathology of human stroke using diffusion and T2-weighted magnetic resonance imaging.

BACKGROUND AND PURPOSE: We sought to identify MRI measures that have high probability in a short acquisition time to predict, at early time points after onset of ischemia, the eventual development of cerebral infarction in clinical patients who suffer occlusion of a cerebral artery. METHODS: We developed an MR tissue signature model based on experimentally derived relationships of the apparent diffusion coefficient of water (ADCw) and T2 to ischemic brain tissue histopathology. In eight stroke patients we measured ADCw and T2 intensity using diffusion-weighted echo-planar imaging (DW-EPI). Tissue signature regions were defined, and theme maps of the ischemic focus at subacute time points after stroke onset were generated. RESULTS: Five MR signatures were identified in human stroke foci: two that may predict either cell recovery or progression to necrosis, one that may mark the transition to cell necrosis, and two that may be markers of established cell necrosis. CONCLUSIONS: An MR tissue signature model of ischemic histopathology using ADCw and T2 can now be tested for its potential to predict reversible and identify irreversible cellular damage in human ischemic brain regions.

Aged↗
PubMed1995

Childhood antecedents of stable positive symptoms in schizophrenia.

For a longitudinal study of 29 males with an initial diagnosis of schizophrenia as young adults, childhood information identified excitable behavior as most strongly related to subsequent positive symptoms. This childhood variable was related to stable but not to unstable positive symptom measures. Further, stable positive symptoms were limited to the subgroup with a history of excitable behavior.

Adolescent↗